There is evidence for both long and short-term changes in synaptic function in several areas of the brain known to mediate reward signals. One type of change occurs in dopamine (DA) neurons of the midbrain. It has been shown that a single, acute exposure to nicotine produces a shift in the subtypes of ionotropic glutamate receptors mediating evoked synaptic transmission. This shift is manifested as an increase in the AMPA/NMDA receptor ratio. This increase is thought to be related to the insertion of postsynaptic AMPA-type receptors that is known to underlie long-term potentiation (LTP). Preliminary data show that in young (21 - 35 postnatal day) C57 mice, a single intraperitoneal injection of nicotine causes an increase in the AMPA/NMDA receptor ratio of evoked glutamate currents in putative midbrain DA neurons. The same effect is also seen in older (60 - 90 postnatal day) mice but with a rightward shift in the dose-response relationship. This suggests that while nicotine is still able to produce the kind of synaptic plasticity that is commonly associated with cellular models of learning and memory (i.e., LTP), the potency of the effect is decreased with age. It is predicted that in younger animals, this type of plasticity will be more sensitive to lower doses of nicotine, and that this relative sensitivity may contribute to the increased vulnerability of adolescents to nicotine addiction. Furthermore, this proposal outlines a course of experiments to determine the effects of exposure to nicotine during this critical developmental period, and to determine if prior exposure to nicotine at a young age lowers the dose threshold for nicotine induced plasticity. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Smoking-related diseases are a major cause of preventable death in the U.S. and around the world. Despite the wealth of information regarding the health risks of tobacco use, many continue to smoke, attesting to the addictive power of nicotine. Research designed to illuminate the mechanisms of nicotine addiction may help in the development of effective methods of prevention and treatment of what is ultimately a life-threatening behavior. [unreadable] [unreadable] [unreadable]